Codeine is used to deal with delicate to reasonable ache and to alleviate cough. Codeine can be used to deal with diarrhea and diarrhea predominant irritable bowel syndrome, though loperamide (which is offered OTC for milder diarrhea), diphenoxylate, paregoric and even laudanum (often known as Tincture of Opium) are extra steadily used to deal with extreme diarrhea.
Formulations
Codeine is marketed as each a single-ingredient drug and together preparations with the analgesic acetaminophen (paracetamol) (as co-codamol, e.g. manufacturers Paracod, Panadeine, Paramol, and the Tylenol with codeine collection together with Tylenol three and four); with the analgesic acetylsalicylic acid (aspirin) (as co-codaprin); or with the NSAID (non-steroidal anti-inflammatory drug) ibuprofen (as Nurofen Plus). These combos present better ache aid than both agent alone (drug synergy). Codeine can be generally marketed in merchandise containing codeine with different ache killers or muscle relaxers, in addition to codeine blended with phenacetin (Emprazil With Codeine No. 1, 2, three, and four), naproxen, indomethacin, diclofenac and others in addition to extra advanced mixtures together with such mixtures as aspirin + paracetamol + codeine ± caffeine ± antihistamines and different brokers corresponding to these talked about above.
Codeine-solely merchandise will be obtained with a prescription as a time launch pill (e.g., Codeine Contin one hundred mg and Perduretas 50 mg). Codeine can be marketed in cough syrups with zero to a half-dozen different lively elements, and a linctus (e.g., Paveral) for the entire makes use of for which codeine is indicated.
Injectable codeine is out there for subcutaneous or intramuscular injection; intravenous injection may cause a severe response that may progress to anaphylaxis. Codeine suppositories are additionally marketed in some countries.
Opposed results
Frequent results aside from analgesia related to using codeine embrace euphoria, itching, nausea, vomiting, drowsiness, dry mouth, miosis, orthostatic hypotension, urinary retention, melancholy, constipation and coughing (which is a paradoxical symptom). Some folks may additionally have an allergic response to codeine, such because the swelling of pores and skin and rashes.
Codeine and morphine in addition to opium have been used for management of diabetes till comparatively lately, and nonetheless are in uncommon instances in some international locations, and the hypoglycaemic impact of codeine, though normally weaker than that of morphine, diamorphine, or hydromorphone, can result in cravings for sugar.
Tolerance to lots of the results of codeine develops with extended use, together with therapeutic effects. The speed at which this happens develops at completely different charges for various results, with tolerance to the constipation-inducing results growing notably slowly for instance.
A doubtlessly severe opposed drug response, as with different opioids, is respiratory depression. This despair is dose-associated and is the mechanism for the possibly deadly penalties of overdose. As codeine is metabolized to morphine, morphine will be handed via breast milk in doubtlessly deadly quantities, fatally miserable the respiration of a breastfed baby.
Withdrawal and dependence
As with different opiate-based mostly ache killers, persistent use of codeine may cause bodily dependence. When bodily dependence has developed, withdrawal signs might happen if an individual out of the blue stops the medication. Withdrawal signs embody: drug craving, runny nostril, yawning, sweating, insomnia, weak point, abdomen cramps, nausea, vomiting, diarrhea, muscle spasms, chills, irritability, and pain. To reduce withdrawal signs, lengthy-time period customers ought to regularly cut back their codeine remedy beneath the supervision of a healthcare professional. A help group known as CodeineFree exists to assist individuals who have discovered themselves depending on codeine.
Pharmacology
Codeine was as soon as thought-about to be a morphine prodrug, because it was thought that its analgesia was due largely to its O-demethylation to the way more highly effective opiate, morphine. Nevertheless, more moderen analysis reveals that eighty% of codeine is conjugated with glucuronic acid to Codeine-6-glucuronide (C6G), which is the metabolite that's most liable for codeine's analgesia, though the relative contributions of codeine-6-glucuronide and morphine to analgesia are unclear and extremely debated. Solely 5% of the dose is O-demethylated to morphine, which in flip is instantly glucuronidated on the three- and 6-place and excreted renally. A portion (~ 15%) of the codeine is N-demethylized to norcodeine. It's much less potent than morphine and has a correspondingly decrease dependence-legal responsibility than morphine. Like all opioids, continued use of codeine induces bodily dependence and may be psychologically addictive. Nonetheless, on account of its low efficiency, the withdrawal signs are comparatively delicate in comparison with carefully associated opioids corresponding to hydrocodone and oxycodone. As such, codeine has a decrease bodily dependence legal responsibility than most different opioids.
A dose of roughly 200 mg (oral) of codeine have to be administered to provide analgesia roughly equal to 30 mg (oral) of morphine (Rossi, 2004). Nonetheless, codeine normally is not utilized in single doses better than 60 mg (and not more than 240 mg in 24 hours). When analgesia past 60 mg of codeine is required, stronger opioids corresponding to hydrocodone or oxycodone are utilized. When used to alleviate dry coughs, codeine is utilized in doses starting from 5-15 mg and is often blended as a syrup with different medicine comparable to promethazine which is an antihistamine with sturdy sedative exercise (some formulations include several types of antihistamines), guaifenesin which is an expectorant, and different drugs. When codeine is not efficient in relieving stronger dry coughs, then the opioid hydrocodone is used instead.
Codeine is metabolized to C6G by uridine diphosphate glucuronosyl transferase UGT2B7, and, since solely about 5% of codeine is metabolized by cytochrome P450 CYP2D6, the present proof is that codeine-6-glucuronide (C6G) is the first energetic compound. Claims concerning the supposed "ceiling impact" of codeine doses appeared to relaxation on the idea that prime doses of codeine saturated CYP2D6, which prevented additional conversion of codeine to morphine, which is just incorrect since we now know that codeine-6-glucuronide (C6G) is the primary metabolite chargeable for codeine's analgesia. There may be additionally no proof that CYP2D6 inhibition is beneficial in treating codeine dependence, although the metabolism of codeine to morphine (and therefore additional metabolism to glucuronide morphine conjugates) does impact the abuse potential of codeine. Nonetheless, CYP2D6 has been implicated within the toxicity and loss of life of neonates when codeine is run to lactating moms, significantly these with elevated 2D6 exercise ("extremely-speedy" metabolisers).
Pharmacokinetics
The conversion of codeine to morphine happens within the liver and is catalysed by the cytochrome P450 enzyme CYP2D6. CYP3A4 produces norcodeine and UGT2B7 conjugates codeine, norcodeine, and morphine to the corresponding three- and 6- glucuronides. Roughly 6-10% of the Caucasians, 2% of Asians, and 1% of Arabs are "poor metabolizers"; they've little CYP2D6, and codeine is much less efficient for analgesia in these sufferers (Rossi, 2004). Srinivasan, Wielbo and Tebbett speculate that codeine-6-glucuronide is chargeable for a big proportion of the analgesia of codeine, and, thus, these sufferers ought to expertise some analgesia. Most of the adversarial results will nonetheless be skilled in poor metabolizers. Conversely, 0.5-2% of the inhabitants are "intensive metabolizers"; a number of copies of the gene for 2D6 produce excessive ranges of CYP2D6 and can metabolize medicine by that pathway extra shortly than others.
Some medicines are CYP2D6 inhibitors and scale back and even fully block the conversion of codeine to morphine. Probably the most nicely-identified of those are in addition to the antihistamine diphenhydramine and the antidepressant, buproprion (Wellbutrin, also referred to as Zyban). Different medication, corresponding to rifampicin and dexamethasone, induce CYP450 isozymes and thus improve the conversion rate.
Since codeine is a prodrug, metabolism variations have the alternative effect. Thus an intensive metabolizer could have opposed results from a fast buildup of codeine metabolites whereas a poor metabolizer might get little or no ache relief. CYP2D6 is dysfunctional in 7% of white and black People, leading to lowered metabolism of codeine. Different people might have extra copies of the CYP2D6 gene, leading to fast metabolism of the goal drug. CYP2D6 metabolizes and prompts codeine into morphine, which then undergoes glucuronidation. Life-threatening intoxication, together with respiratory melancholy requiring intubation, can develop over a matter of days in sufferers who've a number of practical alleles of CYP2D6, leading to extremely-speedy metabolism of opioids resembling codeine into morphine.
The energetic metabolites of codeine, notably morphine, exert their results by binding to and activating the μ-opioid receptor.
Relation to different opiates
Codeine is the beginning materials and prototype of a giant class of primarily delicate to reasonably sturdy opioids equivalent to hydrocodone (1920 in Germany), oxycodone (1916 in Germany), dihydrocodeine (1908 in Germany), and its derivatives corresponding to nicocodeine (1956 in Austria). Different sequence of codeine derivatives embody isocodeine and its derivatives, which have been developed in Germany beginning round 1920. As an analgesic, codeine compares reasonably to different opiates. Associated to codeine in different methods are codoxime, thebacon, Codeine-N-Oxide (Genocodeine), associated to the nitrogen morphine derivatives as is codeine methobromide, and heterocodeine, which is a drug six instances stronger than morphine and seventy two occasions stronger than codeine as a result of a small re-association of the molecule, viz. transferring the methyl group from the three to the 6 place on the morphine carbon skeleton. Medication bearing resemblance to codeine in results as a result of shut structural relationship are variations on the methyl teams on the three place together with ethylmorphine a.k.a. codethyline (Dionine) and benzylmorphine (Peronine). Whereas having no narcotic results of its personal, the essential opioid precursor thebaine differs from codeine solely barely in structure. Pseudocodeine and another comparable alkaloids not presently utilized in medication are present in hint quantities in opium as well.
Historical past
Codeine, or three-methylmorphine, is an alkaloid discovered within the opium poppy, Papaver somniferum var. album, a plant within the papaveraceae family. Opium poppy has been cultivated and utilized all through human historical past for a wide range of medicinal (analgesic, anti-tussive and anti-diarrheal) and hypnotic properties linked to the variety of its energetic parts, which embrace morphine, codeine and papaverine.
Codeine is present in concentrations of 0.9 to 3.zero per cent in opium ready by the latex methodology from unripe pods of Papaver somniferum. The title codeine is derived from the Greek phrase kodeia (κώδεια) for "poppy head". The relative proportion of codeine to morphine, the most typical opium alkaloid at four to 23 per cent, tends to be considerably increased within the poppy straw technique of getting ready opium alkaloids.
Till the start of the nineteenth century, uncooked opium was utilized in numerous preparations often known as laudanum (see Thomas de Quincey's "Confessions of an English Opium-Eater", 1821) and paregoric elixirs, numerous which had been fashionable in England for the reason that starting of the 18th century; the unique preparation appears to have been elaborated in Leiden, the Netherlands round 1715 by a chemist named Lemort; in 1721 the London Pharmocopeia mentions an Elixir Asthmaticum, changed by the time period Elixir Paregoricum ("ache soother") in 1746.
The progressive isolation of opium's a number of energetic parts opened the trail to improved selectivity and security of the opiates-primarily based pharmacopeia.
Morphine had already been remoted in Germany by German pharmacist Friedrich Sertürner in 1804. Codeine was first remoted many years later in 1832 in France by Pierre Robiquet, a French chemist and pharmacist already well-known for the invention of alizarin, essentially the most widespread crimson dye, whereas engaged on refined morphine extraction processes. This paved the way in which for the elaboration of a brand new technology of safer, codeine-primarily based particular antitussive and antidiarrheal formulations.
Codeine is at the moment essentially the most extensively-used opiate on the planet, and is likely one of the mostly used medication general based on quite a few reviews by organizations together with the World Well being Group and its League of Nations predecessor agency. It is likely one of the simplest orally administered opioid analgesics and has a large security margin. Its energy ranges from eight to 12 % of morphine in most individuals; variations in metabolism can change this determine as can different drugs, relying on its route of administration.
Whereas codeine might be straight extracted from opium, its authentic supply, most codeine is synthesized from the far more considerable morphine by way of the method of O-methylation.
By 1972, the consequences of the Nixon Conflict On Medicine had precipitated throughout-the-board shortages of illicit and licit opiates due to a shortage of pure opium, poppy straw, and different sources of opium alkaloids, and the geopolitical scenario was rising tough for the United States. After a big proportion of the opium and morphine within the US Nationwide Stockpile of Strategic & Vital Supplies was tapped as a way to ease extreme shortages of medicinal opiates - the codeine-primarily based antitussives specifically - in late 1973, researchers had been tasked with discovering a strategy to synthesize codeine and its derivatives. They rapidly succeeded utilizing petroleum or coal tar and a course of developed on the United States' Nationwide Institutes of Health.
Quite a few codeine salts have been ready for the reason that drug was discovered. Probably the most generally used are the hydrochloride (freebase conversion ratio 0.805), phosphate (0.736), sulphate (0.859), and citrate (0.842). Others embody a salicylate NSAID, codeine salicylate (0.686), and at the least 4 codeine-primarily based barbiturates, the cyclohexenylethylbarbiturate (0.559), cyclopentenylallylbarbiturate (0.561), diallylbarbiturate (0.561), and diethylbarbiturate (0.619).
Leisure use
Codeine can be utilized as a leisure drug.
In some international locations, cough syrups and tablets containing codeine can be found with out prescription; some potential leisure customers are reported to purchase codeine from a number of pharmacies in order to not arouse suspicion. A heroin addict could use codeine to keep off the consequences of a withdrawal.
Codeine can also be obtainable along side the anti-nausea remedy promethazine within the type of a syrup. Model named as Phenergan with Codeine or in generic kind as promethazine with codeine. Known as 'syrup', this remedy is shortly turning into probably the most generally misused codeine preparations.
Codeine can be demethylated by response with pyridine to illicitly synthesize morphine, which may then be acetylated to make heroin (diacetylmorphine). Pyridine is poisonous and presumably carcinogenic, so morphine illicitly produced on this method (and probably contaminated with pyridine) could also be notably harmful. Codeine will also be became α-chlorocodide, which is used within the clandestine synthesis of desomorphine (Permonid) (desomorphine attracted consideration in 2010 in Russia resulting from an upsurge in clandestine manufacturing, presumably as a result of its comparatively easy synthesis from codeine. The drug is definitely constituted of codeine, iodine and purple phosphorus, in the same course of to the manufacture of methamphetamine from pseudoephedrine, however desomorphine made this fashion is very impure and contaminated with numerous poisonous and corrosive byproducts.).
Detection
Codeine and/or its main metabolites could also be quantitated in blood, plasma or urine to watch remedy, affirm a analysis of poisoning or help in a medicolegal dying investigation. Drug abuse screening packages usually check urine, hair, sweat or oral fluid. Many industrial opiate screening assessments directed at morphine cross-react appreciably with codeine and its metabolites, however chromatographic strategies can simply distinguish codeine from different opiates and opioids. You will need to observe that codeine utilization ends in important quantities of morphine as an excretion product. Moreover, heroin incorporates codeine (or acetylcodeine) as an impurity and its use will lead to excretion of small quantities of codeine. Poppy seed meals characterize one more supply of low ranges of codeine in a single's biofluids. Blood or plasma codeine concentrations are usually within the 50-300 µg/L vary in individuals taking the drug therapeutically, seven hundred-7000 µg/L in continual customers and one thousand-10,000 µg/L in instances of acute deadly overdosage.
